The present invention relates to drug and gene delivery and pertains particularly to an apparatus and method for combining electroporation and iontophoresis for the transdermal delivery of genes, drugs and other molecules.
The medical community has long sought improved methods of transdermal delivery of medications, drugs and other molecules and fluids without physical penetration or invasion of the tissue surface. A number of applicant's prior patents are disclosed apparatus and methods for the transdermal delivery of molecules such as drugs, immunizing agents, and genes into underlying tissue, cells, and to remote tissue.
In U.S. Pat. No. 5,318,514, an apparatus is disclosed for an applicator for delivery of a fluid medium carrying preselected molecules to a tissue surface and thereafter applying electrical signals by means of electrodes applied to the surface tissue. The field is applied at a predetermined strength and duration in order to make the walls of the tissue surface transiently permeable to permit the molecules to pass through the tissue surface into underlying tissue. Further electroporation can enable the molecules to enter preselected cells without damaging them.
U.S. Pat. No. 5,304,120 discloses a catheter device is inserted into a selected blood vessel of a patient and advanced to a location within the vessel where endothelial cells on the inner wall of the vessel are to be treated. Once in place, the catheter device is expanded so that a plurality of circumferentially spaced electrodes carried thereby are in contact with the inner wall of the blood vessel. A fluid medium is then infused into the blood vessel adjacent the electrodes. A power pack connected to the electrodes is energized to apply a predetermined electric signal to the electrodes. This subjects the endothelial cells to electric fields of predetermined amplitude and duration to make the walls of the endothielial cells transiently permeable to permit therapeutic genes or drugs to enter the endothelial cells without killing them.
U.S. Pat. No. 5,462,520 discloses a method of molecular delivery which comprises encapsulating molecules to be delivered in a microbubble carrier, contacting a selected area of a tissue surface with a solution of the encapsulated molecules, and applying an electric field of sufficient amplitude to induce the tissue and the membrane of the microbubble to enable diffusion of molecules from the microbubble through the tissue.
U.S. Pat. No. 5,464,386 discloses a method of transdermal molecular delivery which comprises the steps of encapsulating molecules to be delivered in a vesicle, contacting a selected area of a tissue surface with a solution of the vesicles, and applying a pulsed electric field of sufficient amplitude to induce dielectric breakdown of the stratum corneum and to induce transport of the intact vesicle through the pores in the stratum corneum into the underlying tissue to enable diffusion of molecules into the tissue.
U.S. Pat. No. 5,688,233 discloses a method of transdermal molecular delivery wherein molecules to be delivered are mixed with particles. A selected area of a skin surface is contacted with the particles and molecules. A pulsed electric field of sufficient amplitude and duration to induce dielectric breakdown of the stratum corneum is applied and a pressure is applied to the molecules to force transport of the molecules through the pores in the stratum corneum into the underlying skin.
One difficulty with the prior apparatus is that the stratum corneum (SC) which consists of a thin layer of dead cells with a high electrical resistance presents a major obstacle to the administration of drugs and genes transdermally. This layer can be perforated by the administration of short high voltage electrical field pulses, which creates a dielectric breakdown of the stratum corneum forming pores which can allow the passage of molecules. However, in order to transport molecules and solutions containing molecules through the pores, a driving force has been found to be needed. This driving force can be provided by any number of mechanisms as discussed in the aforementioned patents including iontophoresis. However the known electroporation apparatus and methods for efficient application of these principles is limited.
Among the prior art relating generally to this field is U.S. Pat. No. 5,019,034, which discloses an alternative to the traditional syringe and gun injection of medications by using a high voltage, short duration electrical pulses on the skin surface to produce electroporation of the tissue to enable drugs and medication to pass into the tissue. However, this disclosed apparatus and methods have limited effectiveness.
Electroporation is typically carried out by applying high voltage pulses between a pair of electrodes which are applied to the tissue surface. The voltage must be applied in proportional to the distance between the electrodes. When the space between the electrodes is too great, the generated electric field penetrates deep into the tissue where it causes unpleasant nerve and muscle reaction.
While electroporation provides new pathways through the stratum corneum for passages of molecules, it does not provide a needed driving force. It is desirable that electroporation be combined with techniques for providing a driving force such as electroincorporation, pressure or concentration gradient, sonophoresis or iontophoresis.
It is known that iontophoresis wherein low voltage is applied between widely spaced electrodes for a long period of time can transport charged molecules through existing pathways such as hair follicles and sweat glands. However, the volumes of molecules transported is very small, and insufficient for many applications. Combining electroporation and iontophoresis can increase the amount transported initially while the created pathways are open. However, the paths created by the electroporation stay open for a short period of time and then close.
It is desirable that a simpler apparatus and method be available to combine both electroporation and iontophoresis without the unpleasant side effects for transport molecules through or into the stratum corneum.